1. Field of the Invention
The present disclosure relates to the preparation of iron oxide nanoparticles in the form of an aqueous dispersion, as well as in the form of powder, by salt-assisted solid-state synthesis.
2. Related Art
The three most commonly used iron oxides are γ-Fe2O3 (Maghemite), α-Fe2O3 (Hematite) and Fe3O4 (Magnetite). These iron oxides are known to have many important technological applications.
Magnetic iron oxide nanoparticle dispersions, commercially known as “Ferrofluid”, have been used widely in, for example, rotary shaft sealing for vacuum vessels, oscillation damping for various electronic instruments, and position sensing for avionics, robotics, machine tool, and automotive (See U.S. Pat. No. 5,322,756; U.S. Pat. No. 5,858,595; K. Raj, R. Moskowitz, J. Magn. Magn. Mater., 85, 233 (1990)).
The use of iron oxide nanoparticles in clinical medicine is an important field in diagnostic medicine and drug delivery. Maghemite and magnetite nanoparticles, with particle size smaller than 20 nm, are superparamagnetic. These particles interfere with an external homogeneous magnetic field and can be positioned magnetically in a living body, facilitating magnetic resonance imaging (MRI) for medical diagnosis (see U.S. Pat. No. 6,123,920; U.S. Pat. No. 6,207,134; U.S. Pat. No. 5,424,419; U.S. Pat. No. 4,827,945; U.S. Pat. No. 6,423,296; and D. K. Kim, et al, J. Magn. Magn. Mater., 225, 256 (2001), the complete article is incorporated herein by reference in its entirety); C. C. Berry et al. Phys. D: Appl. Phys. 36, R198 (2003)), and AC magnetic field induced excitation for cancer therapy (see U.S. Pat. No. 6,165,440; U.S. Pat. No. 6,167,313, which is incorporated herein by reference in its entirety; A. Jordan, et al, J. Magn. Magn. Mater., 201, 413 (1999)). All of these medicinal and technological applications of magnetic iron oxide fluids require that the magnetic particle size is within the single domain size range and the overall particle size distribution is narrow so that the particles have uniform physical properties, biodistribution, bioelimination and contrast effects. For example, for medicinal applications, mean particle sizes should generally be in the range 2 to 15 nm and, for use as blood pool agents, the mean overall particle size including any coating materials should preferably be below 30 nm. However, producing particles with the desired size, acceptable size distribution, good aqueous dispersibility without particle aggregation has constantly been a problem.
Two methods have heretofore been generally used to produce iron oxide aqueous dispersions.
In the first method, a dispersion is prepared by milling, or by a so-called “mechanochemical” process. This solid-state synthesis is particularly suitable for large-scale production of nanostructured materials, because of its simplicity and low cost. It is, in general, most simply done by grinding an iron oxide in a suitable liquid vehicle in the presence of a dispersing agent or surfactant to obtain a stable colloidal. This method is known to have at least three problems. First, a typical grinding or milling operation can be a time-intensive process, and grinding or milling times of 120 hours or more are typically required to produce magnetic fluids. (See U.S. Pat. No. 3,215,572). Such long times are required to produce small enough particles to enable the formation of a stable colloid. Second, the choice of dispersing agents or surfactants is difficult, as the correct or enabling surfactant is often found through trial-and-error. Third, the surfactant may degrade or cause adverse chemical reactions during its application.
In one known application of this method, although organic solvent-free solid-state synthesis of maghemite nanoparticles with an average diameter of 15 nm was reported by high-energy ball-milling with iron powder and water (See R. Janot, et al. J. Alloy Comp. 333, 302 (2002)), at least 48 hours were needed for the milling process, and the product was severely aggregated. While milling in an ethanol medium can be used to produce maghemite from hematite (See N. Randrianantoandro, et al. Mater. Lett. 47,150 (2001)), the product is normally an undesirable mixture of hematite and maghemite phases. Lin et al. used anhydrous ferric and ferrous chlorides as reactants for the solid-state synthesis of magnetite nanoparticles with an average particle size of 14.8 nm, but again, the method suffered from a long milling time of over 72 hours. (See C. R. Lin, et al. Mater. Letts. 60,447 (2006)).
The second method, chemical precipitation of the nanoparticles, is probably the method most often used to prepare magnetic nanoparticles in colloids. Different procedures have been developed to achieve this goal. In general, each of these procedures start with a mixture of FeCl2 and FeCl3 and water. Co-precipitation occurs with the addition of sodium hydroxide or ammonium hydroxide, and then the system is subjected to different procedures for peptization, magnetic separation, filtration and finally dilution (See U.S. Pat. No. 4,452,773). The nanoparticles obtained by chemical precipitation are often modified by coating with a polymer or other surfactant as stabilizer in forming an aqueous dispersion. In fact, all Superparamagnetic Iron Oxide (SPIO) or Ultrafine Superparamagnetic Iron Oxide (USPIO) MRI contrast agents presently approved for clinical usage, as well as most of the contrast agents currently under development, are stabilized by the polymer dextran or its derivatives. (See A. H. Dutton, et al, Proc. Natl. Acad. Sci. USA 76, 3392 (1979)). Unfortunately, the polymer coating significantly increases the nanoparticles' overall sizes, and therefore may limit their tissue distribution, penetration, and metabolic clearance. Polymer-coated particles are often up-taken rapidly by the reticuloendothelial system, such as Kupffer cells of the liver. In general, the biodistribution of these polymer-based nanoparticles is mainly influenced by their size and surface chemistry (See R. Weissleder, et al, Radiology, 175, 489 (1990); F. Y. Cheng, et al, Biomaterials 26, 729 (2005)). It has been shown in the kinetic studies of the liver MR contrast agents that the particle's hydrodynamic size may play an important role: (See K. Lind, et al, J. Drug Target., 10, 221 (2002)). Larger polymer-coated SPIO particles (about 50 nm; e.g. Ferridex®, Berlex Lab., USA) were mainly trapped in the liver, while smaller sizes (about 30 nm; e.g. Combidex®, Advanced Magnetics, Cambridge, Mass.; Sinerem®, Laboratoire Guerbet, Fr) are useful for imaging the lymph node systems.
Thus, as described above, both known methods for producing iron oxide aqueous dispersions are either time-consuming, or involve surfactant contamination, or both. Attempts to rapidly produce an aqueous dispersion of SPIO or USPIO nanoparticles without the use of a surfactant have heretofore shown very limited success.
Various other known methods of producing iron oxide nanoparticles are problematic for the following reasons.
A number of patents and publications to Sun (U.S. Pat. No. 7,128,891; U.S. Pat. No. 6,962,685; U.S. Patent Application Publication No. 2007/0056401) describe methods in which an iron salt, alcohol, carboxylic acid, and amine are mixed in an ether solvent and heated to reflux. The mixture is then treated with ethanol, and the resulting powder is again dissolved in hexane in the presence of acid and amine, re-precipitated with ethanol, and then oxidized while being held at a temperature of 250° C. or 500° C., to produce γ-Fe2O3 or α-Fe2O3 nanoparticles, respectively. This process requires repetition of an undesirable number of steps, and requires centrifugation to remove impurities and undesired precipitates.
U.S. Patent Application Publication No. 2005/0271593 to Yeh et al. describes a method of preparing water-soluble and dispersed Fe3O4 nanoparticles. The method involves mixing solutions containing Fe2+ and Fe3+ at pre-determined concentrations, adding organic acids as adherents, adjusting the pH value of the solution to produce a precipitate, again adding organic acids as adherents, and then adding water and an organic solvent to remove excess organic acid. Undesirably, this process requires the preparation of solutions containing Fe2+ and Fe3+ at pre-determined concentrations, and does not isolate γ-Fe2O3 from α-Fe2O3 nanoparticles.
Similarly, U.S. Patent Application Publication No. 2006/0141149 to Chen et al. describes a method of forming a superparamagnetic nanoparticle. The method involves mixing aqueous solutions containing Fe2+ and Fe3+ ions with an alkalai, and then subjecting the mixture to ultrasonic vibration, to produce both Fe3O4 and Fe2O3 nanoparticles. Undesirably, this process requires the preparation of solutions containing Fe2+ and Fe3+ at pre-determined concentrations, and does not isolate Fe3O4, γ-Fe2O3, or α-Fe2O3 nanoparticles.
U.S. Patent Application Publication No. 2007/0059775 to Hultman et al. describes a method of producing an iron oxide nanoparticle, in which iron pentacarbonyl is injected into a reaction mixture comprising oleic acid and trioctylamine. Undesirably, in order to be made water soluble, the resulting nanoparticles must be encapsulated in a phospholipid micelle. As in the methods described above, the encapsulation results in an undesirable enlargement of the size of the nanoparticles. Moreover, this encapsulation requires tedious preparation of the preselected micelle.
U.S. Patent Application Publication No. 2006/0204438 to Cho et al. describes a method of preparing water-soluble iron oxide nanoparticles. The method involves dissolving polyvinylprolidone in dimethylformamide, refluxing, heating, adding thereto iron pentacarbonyl; cooling, and then dialysis performed in an ultrapure nitrogen atmosphere. Undesirably, this process: requires long preparation times (the pentacarbonyl addition step requires two hours of stirring, and the dialysis step requires 24 hours to remove unreacted polymers and solvents); requires the use of an ultrapure nitrogen atmosphere; and, uses a solvent (dimethylformamide) known to be hazardous to humans and subject to dangerous exothermic decomposition.